There have been no specific guidelines regarding which genes should be tested in the clinical setting for Parkinson's disease (PD) or parkinsonism. We evaluated the types of clinical genetic testing ...offered for PD as the first step of our gene curation.
The National Institutes of Health (NIH) Genetic Testing Registry (GTR) was queried on 12/7/2020 to identify current commercial PD genetic test offerings by clinical laboratories, internationally.
We identified 502 unique clinical genetic tests for PD, from 28 Clinical Laboratory Improvement Amendments (CLIA)-approved clinical laboratories. These included 11 diagnostic PD panels. The panels were notable for their differences in size, ranging from 5 to 62 genes. Five genes for variant query were included in all panels (SNCA, PRKN, PINK-1, PARK7 (DJ1), and LRRK2). Notably, the addition of the VPS35 and GBA genes was variable. Panel size differences stemmed from inclusion of genes linked to atypical parkinsonism and dystonia disorders, and genes in which the link to PD causation is controversial.
There is an urgent need for expert opinion regarding which genes should be included in a commercial laboratory multi-gene panel for PD.
Osteomyelitis is a devastating disease caused by microbial infection of bone. While the frequency of infection following elective orthopedic surgery is low, rates of reinfection are disturbingly ...high.
is responsible for the majority of chronic osteomyelitis cases and is often considered to be incurable due to bacterial persistence deep within bone. Unfortunately, there is no consensus on clinical classifications of osteomyelitis and the ensuing treatment algorithm. Given the high patient morbidity, mortality, and economic burden caused by osteomyelitis, it is important to elucidate mechanisms of bone infection to inform novel strategies for prevention and curative treatment. Recent discoveries in this field have identified three distinct reservoirs of bacterial biofilm including:
abscess communities in the local soft tissue and bone marrow, glycocalyx formation on implant hardware and necrotic tissue, and colonization of the osteocyte-lacuno canalicular network (OLCN) of cortical bone. In contrast,
intracellular persistence in bone cells has not been substantiated in vivo, which challenges this mode of chronic osteomyelitis. There have also been major advances in our understanding of the immune proteome against
, from clinical studies of serum antibodies and media enriched for newly synthesized antibodies (MENSA), which may provide new opportunities for osteomyelitis diagnosis, prognosis, and vaccine development. Finally, novel therapies such as antimicrobial implant coatings and antibiotic impregnated 3D-printed scaffolds represent promising strategies for preventing and managing this devastating disease. Here, we review these recent advances and highlight translational opportunities towards a cure.
Molybdenum (Mo) is a popular paleoproxy for tracking the spatiotemporal pattern of euxinic (anoxic and sulfidic) conditions in the ancient ocean, yet surprisingly little is known about the processes ...leading to its fixation under sulfidic conditions. Pyrite has been proposed to be the main host phase for Mo sequestration. To clarify the role played by pyrite, and thus to refine the utility of this paleoproxy, modern and ancient samples from six different study sites were analyzed, all representing euxinic conditions, using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). Although pyrite often shows substantial enrichments relative to average crust and even matrix samples of similar size, our results show that most of the Mo in euxinic muds and shales is found in the non-pyrite matrix (80–100%) and not in the pyrite grains (0–20%)—simply because the volume of matrix dominates the bulk sediments/rocks. A relationship between the percent of Mo hosted by pyrite and the sulfur isotope composition of that pyrite is observed and can be linked to post-depositional alteration. Specifically, the oldest, typically most altered samples, show the highest δ34S values because of limited sulfate availability at the time of their formation in the early ocean. In these old samples, the relatively small amount of Mo sequestered initially within pyrite is more likely to have been released to the matrix during the strong recrystallization overprints that these rocks have disproportionately suffered. Despite the universal importance of appreciable H2S availability during Mo uptake, we conclude that pyrite should be viewed as a nontrivial sink for Mo but clearly not the primary host in most euxinic shales and rather suggest that other burial pathways should be emphasized in future studies of the mechanisms of Mo sequestration in such settings.
An individual's rate of aging directly influences his/her susceptibility to morbidity and mortality. Thus, quantifying aging and disentangling how various factors coalesce to produce between-person ...differences in the rate of aging, have important implications for potential interventions. We recently developed and validated a novel multi-system-based aging measure, Phenotypic Age (PhenoAge), which has been shown to capture mortality and morbidity risk in the full US population and diverse subpopulations. The aim of this study was to evaluate associations between PhenoAge and a comprehensive set of factors, including genetic scores, childhood and adulthood circumstances, and health behaviors, to determine the relative contributions of these factors to variance in this aging measure.
Based on data from 2,339 adults (aged 51+ years, mean age 69.4 years, 56% female, and 93.9% non-Hispanic white) from the US Health and Retirement Study, we calculated PhenoAge and evaluated the multivariable associations for a comprehensive set of factors using 2 innovative approaches-Shapley value decomposition (the Shapley approach hereafter) and hierarchical clustering. The Shapley approach revealed that together all 11 study domains (4 childhood and adulthood circumstances domains, 5 polygenic score PGS domains, and 1 behavior domain, and 1 demographic domain) accounted for 29.2% (bootstrap standard error = 0.003) of variance in PhenoAge after adjustment for chronological age. Behaviors exhibited the greatest contribution to PhenoAge (9.2%), closely followed by adulthood adversity, which was suggested to contribute 9.0% of the variance in PhenoAge. Collectively, the PGSs contributed 3.8% of the variance in PhenoAge (after accounting for chronological age). Next, using hierarchical clustering, we identified 6 distinct subpopulations based on the 4 childhood and adulthood circumstances domains. Two of these subpopulations stood out as disadvantaged, exhibiting significantly higher PhenoAges on average. Finally, we observed a significant gene-by-environment interaction between a previously validated PGS for coronary artery disease and the seemingly most disadvantaged subpopulation, suggesting a multiplicative effect of adverse life course circumstances coupled with genetic risk on phenotypic aging. The main limitations of this study were the retrospective nature of self-reported circumstances, leading to possible recall biases, and the unrepresentative racial/ethnic makeup of the population.
In a sample of US older adults, genetic, behavioral, and socioenvironmental circumstances during childhood and adulthood account for about 30% of differences in phenotypic aging. Our results also suggest that the detrimental effects of disadvantaged life course circumstances for health and aging may be further exacerbated among persons with genetic predisposition to coronary artery disease. Finally, our finding that behaviors had the largest contribution to PhenoAge highlights a potential policy target. Nevertheless, further validation of these findings and identification of causal links are greatly needed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Wheat powdery mildew is one of the most destructive diseases threatening global wheat production. The wild relatives of wheat constitute rich sources of diversity for powdery mildew resistance. Here, ...we report the map-based cloning of the powdery mildew resistance gene Pm13 from the wild wheat species Aegilops longissima. Pm13 encodes a mixed lineage kinase domain-like (MLKL) protein that contains an N-terminal-domain of MLKL (MLKL_NTD) domain in its N-terminus and a C-terminal serine/threonine kinase (STK) domain. The resistance function of Pm13 is validated by mutagenesis, gene silencing, transgenic assay, and allelic association analyses. The development of introgression lines with significantly reduced chromosome segments of Ae. longissima encompassing Pm13 enables widespread deployment of this gene into wheat cultivars. The cloning of Pm13 may provide valuable insights into the molecular mechanisms underlying Pm13-mediated powdery mildew resistance and highlight the important roles of kinase fusion proteins (KFPs) in wheat immunity.
Abstract Powdery mildew is a devastating disease that affects wheat yield and quality. Wheat wild relatives represent valuable sources of disease resistance genes. Cloning and characterization of ...these genes will facilitate their incorporation into wheat breeding programs. Here, we report the cloning of Pm57 , a wheat powdery mildew resistance gene from Aegilops searsii . It encodes a tandem kinase protein with putative kinase-pseudokinase domains followed by a von Willebrand factor A domain (WTK-vWA), being ortholog of Lr9 that mediates wheat leaf rust resistance. The resistance function of Pm57 is validated via independent mutants, gene silencing, and transgenic assays. Stable Pm57 transgenic wheat lines and introgression lines exhibit high levels of all-stage resistance to diverse isolates of the Bgt fungus, and no negative impacts on agronomic parameters are observed in our experimental set-up. Our findings highlight the emerging role of kinase fusion proteins in plant disease resistance and provide a valuable gene for wheat breeding.
Major clinical issues in bladder cancer include the identification of prediction markers and novel therapeutic targets for invasive bladder cancer. In the current study, we describe the isolation and ...characterization of a tumor-initiating cell (T-IC) subpopulation in primary human bladder cancer, based on the expression of markers similar to that of normal bladder basal cells (Lineage-CD44⁺CK5⁺CK20⁻). The bladder T-IC subpopulation was defined functionally by its enriched ability to induce xenograft tumors in vivo that recapitulated the heterogeneity of the original tumor. Further, molecular analysis of more than 300 bladder cancer specimens revealed heterogeneity among activated oncogenic pathways in T-IC (e.g., 80% Gli1, 45% Stat3, 10% Bmi-1, and 5% β-catenin). Despite this molecular heterogeneity, we identified a unique bladder T-IC gene signature by gene chip analysis. This T-IC gene signature, which effectively distinguishes muscle-invasive bladder cancer with worse clinical prognosis from non-muscle-invasive (superficial) cancer, has significant clinical value. It also can predict the progression of a subset of recurring non-muscle-invasive cancers. Finally, we found that CD47, a protein that provides an inhibitory signal for macrophage phagocytosis, is highly expressed in bladder T-ICs compared with the rest of the tumor. Blockade of CD47 by a mAb resulted in macrophage engulfment of bladder cancer cells in vitro. In summary, we have identified a T-IC subpopulation with potential prognostic and therapeutic value for invasive bladder cancer.
Males and females with alcohol dependence have distinct mental health and cognitive problems. Animal models of addiction postulate that the underlying neurobiological mechanisms are partially ...distinct, but there is little evidence of sex differences in humans with alcohol dependence as most neuroimaging studies have been conducted in males. We examined hippocampal and amygdala subregions in a large sample of 966 people from the ENIGMA Addiction Working Group. This comprised 643 people with alcohol dependence (225 females), and a comparison group of 323 people without alcohol dependence (98 females). Males with alcohol dependence had smaller volumes of the total amygdala and its basolateral nucleus than male controls, that exacerbated with alcohol dose. Alcohol dependence was also associated with smaller volumes of the hippocampus and its CA1 and subiculum subfield volumes in both males and females. In summary, hippocampal and amygdalar subregions may be sensitive to both shared and distinct mechanisms in alcohol-dependent males and females.
The past decade has witnessed a rapid evolution in identifying more versatile clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas) nucleases and their ...functional variants, as well as in developing precise CRISPR/Cas-derived genome editors. The programmable and robust features of the genome editors provide an effective RNA-guided platform for fundamental life science research and subsequent applications in diverse scenarios, including biomedical innovation and targeted crop improvement. One of the most essential principles is to guide alterations in genomic sequences or genes in the intended manner without undesired off-target impacts, which strongly depends on the efficiency and specificity of single guide RNA (sgRNA)-directed recognition of targeted DNA sequences. Recent advances in empirical scoring algorithms and machine learning models have facilitated sgRNA design and off-target prediction. In this review, we first briefly introduce the different features of CRISPR/Cas tools that should be taken into consideration to achieve specific purposes. Secondly, we focus on the computer-assisted tools and resources that are widely used in designing sgRNAs and analyzing CRISPR/Cas-induced on- and off-target mutations. Thirdly, we provide insights into the limitations of available computational tools that would help researchers of this field for further optimization. Lastly, we suggest a simple but effective workflow for choosing and applying web-based resources and tools for CRISPR/Cas genome editing.
Phosphorus is considered the ultimate limiting nutrient in the oceans over geological timescales. Phosphate (PO43-) availability consequently exerts control on the global carbon cycle and ...atmospheric/oceanic redox conditions over million-year timescales. Despite its importance, there are no established tools that can directly and continuously reconstruct oceanic phosphate concentrations through time. Here, we report a new approach to carbonate-associated phosphate (CAP) extraction and a series of experiment-based constraints for using CAP as a tool for reconstructing ancient oceanic phosphate concentrations. Experimental work shows that phosphate is incorporated into carbonate at various concentrations as a function of solution phosphate concentration, pH, temperature, and carbonate mineralogy. It is recommended here that in order to selectively extract CAP, carbonate sediments should be partially leached in order to avoid contamination from non-carbonate phases. Analyses of recent and ancient carbonates indicate that CAP values may shift during neomorphic aragonite-to-calcite transformations and secondary alteration. Diagenetic carbonate concretions in the organic- and phosphorus-rich Monterey Formation yield elevated CAP values that correlate with indicators of significant organic matter oxidation; however, this pattern was not observed for geologically young, weakly altered carbonates in the Marion Platform (north-eastern Australian shelf). These observations suggest CAP can yield reliable information on secular variation in oceanic phosphate concentrations and semi-quantitative reconstructions, if samples are characterised mineralogically and screened for secondary alteration.
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